Safety evaluation of a human chimeric monoclonal antibody that recognizes the extracellular loop domain of claudin-2
Safety evaluation of a human chimeric monoclonal antibody that recognizes the extracellular loop domain of claudin-2
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DOI：
10.1016/j.ejps.2018.02.016
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发表时间：
2018-05-30
影响因子：
4.6
通讯作者：
Kondoh, Masuo
中科院分区：
文献类型：
--
作者：
Hashimoto, Yosuke;Hata, Tomoyuki;Kondoh, Masuo
Claudin-2(CLDN-2)是一种具有四跨膜结构域的致孔紧密连接蛋白，参与了某些肿瘤的发生和转移。尽管CLDN-2在肝和肾的紧密连接处高度表达，但CLDN-2是否是癌症治疗的安全靶点仍不清楚。我们最近制备了一种能识别人和小鼠CLDN-2胞外区的鼠单抗(mAb，克隆1A2)。在这里，我们使用1A2作为模型治疗性抗体，研究了CLDN-2靶向肿瘤治疗的安全性。由于大多数人治疗性单抗都是IgG1亚型，可以诱导抗体依赖的细胞毒作用，因此我们产生了人-大鼠嵌合的1A2(Xi-1A2)形式。Xi-1A2在表达CLDN-2的细胞中激活Fcγ受体IIIa，提示Xi-1A2可能具有抗体依赖性的细胞毒作用。在静脉注射后24小时，Xi-1A2在肝、肾和荷CLDN-2纤维肉瘤细胞小鼠的肿瘤组织中分布。用Xi-1A2治疗移植的小鼠，肿瘤生长减弱，没有明显的不良反应，如体重和肝肾损伤的生化指标的变化。这些结果支持Xi-1A2作为安全的CLDN-2靶向肿瘤治疗的首选候选单抗。
Claudin-2 (CLDN-2), a pore-forming tight junction protein with a tetra-transmembrane domain, is involved in carcinogenesis and the metastasis of some cancers. Although CLDN-2 is highly expressed in the tight junctions of the liver and kidney, whether CLDN-2 is a safe target for cancer therapy remains unknown. We recently generated a rat monoclonal antibody (mAb, clone 1A2) that recognizes the extracellular domains of human and mouse CLDN-2. Here, we investigated the safety of CLDN-2-targeted cancer therapy by using 1A2 as a model therapeutic antibody. Because most human therapeutic mAbs are IgG1 subtype that can induce antibody-dependent cellular cytotoxicity, we generated a human-rat chimeric IgG1 form of 1A2 (xi-1A2). xi-1A2 activated Fc gamma receptor IIIa in the presence of CLDN-2-expressing cells, indicating that xi-1A2 likely exerts antibody-dependent cellular cytotoxicity. At 24 h after its intravenous injection, xi-1A2 was distributed into the liver, kidney, and tumor tissues of mice bearing CLDN-2-expressing fibrosarcoma cells. Treatment of the xenografted mice with xi-1A2 attenuated tumor growth without apparent adverse effects, such as changes in body weight and biochemical markers of liver and kidney injury. These results support xi-1A2 as the lead candidate mAb for safe CLDN-2-targeted cancer therapy.